Naloxone formulations for sublingual and/or buccal administration

ABSTRACT

Liquid, gel, and semi-solid compositions containing naloxone base, or isomers or derivatives thereof, with one or more non-aqueous solvents, and optional viscosity adjusting agents, are provided. Methods of treating an individual exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose including administering a liquid, gel, or semi-solid formulation containing a solution of naloxone base, or an isomer or a derivative thereof, in one or more non-aqueous solvents, are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 62/808,363, filed on Feb. 21, 2019, and U.S. Provisional ApplicationNo. 62/808,386, filed on Feb. 21, 2019, both of which are incorporatedby reference herein in their entireties.

FIELD OF THE INVENTION

The invention is directed to liquid, gel, or semi-solid compositionscontaining naloxone base, or isomers or derivatives thereof, with one ormore non-aqueous solvents. The invention is further directed to methodsof treating respiratory depression associated with known or suspectedopioid overdoses.

BACKGROUND OF THE INVENTION

An opioid overdose is toxicity due to excessive opioids. Symptomsinclude, but are not limited to, insufficient breathing, small pupils,and unconsciousness. Among individuals who initially survive an opioidoverdose, medical complications can include, but are not limited to,rhabdomyolysis, pulmonary edema, compartment syndrome, and permanentbrain damage. See, e.g., E. W. Boyer, Management of opioid analgesicoverdose, 367 NEW ENGLAND J. MEDICINE 146 (2012), incorporated byreference herein in its entirety. Risk factors for opioid overdoseinclude, but are not limited to, opioid dependence, injecting opioids,using high doses of opioids, mental disorders, and use of opioidstogether with alcohol, benzodiazepines, or cocaine. See, e.g., T. W.Park, Understanding Risk Factors for Opioid Overdose in ClinicalPopulations to Inform Treatment and Policy, 10 J. ADDICTION MEDICINE 369(2016), incorporated by reference herein in its entirety. Opioid usedisorders resulted in 122,000 deaths globally in 2015, up from 18,000deaths in 1990. See, e.g., GBD 2015 Mortality and Causes of DeathCollaborators, Global, regional, and national life expectancy, all-causemortality, and cause-specific mortality for 249 causes of death,1980-2015: a systematic analysis for the Global Burden of Disease Study2015, 388 LANCET 1459 (2016), incorporated by reference herein in itsentirety. Further, the rate of opioid overdoses has tripled since 2000and more deaths were reported in the United States in 2017 than in anyprevious year on record. In 2017, opioid overdose deaths accounted for47,600 deaths in the United States. See, e.g., Lawrence Scholl, et al.,Drug and Opioid-Involved Overdose Deaths—United States, 2013-2017, 67MORBIDITY & MORTALITY WEEKLY REPORT 1419 (2019), incorporated byreference herein in its entirety.

Initial treatment of an individual exhibiting symptoms of opioidoverdose involves supporting the individual's breathing and providingoxygen. See, e.g., A. R. de Caen, et al., Part 12: Pediatric AdvancedLife Support: 2015 American Heart Association Guidelines Update forCardiopulmonary Resuscitation and Emergency Cardiovascular Care, 18(Suppl. 2) CIRCULATION S526 (2015), incorporated by reference herein inits entirety. Naloxone is then recommended among those who are notbreathing in order to reverse the opioid effects. Among individuals whorefuse to go to a hospital following reversal, the risks of a pooroutcome in the short term appear to be low. See, e.g., R. Chou, et al.,Management of Suspected Opioid Overdose With Naloxone in Out-of-HospitalSettings: A Systematic Review, 167 ANNALS OF INTERNAL MEDICINE 867(2017), incorporated by reference herein in its entirety.

Naloxone, also known as N-allylnoroxymorphone or17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, is a lipophiliccompound that acts as a non-selective and competitive opioid receptorantagonist. Naloxone is a synthetic morphinan derivative derived fromoxymorphone. Naloxone is highly lipophilic, which allows naloxone torapidly penetrate the brain and to achieve a higher brain-to-serum ratiothan that of morphine. See, e.g., Reginald Dean, et al., OpiateReceptors and Antagonists: From Bench to Clinic, S PRINGER SCI. &BUSINESS MEDIA 514 (2009), incorporated by reference herein in itsentirety. Naloxone base has the following structure:

Naloxone hydrochloride is currently available at many pharmacies as(Narcan®) a spray formulation for intranasal (IN) administration and asan intramuscular injection (IM) using an autoinjector (Evzio®). However,the high cost per dosage unit of Narcan® and Evzio® relegates use mainlyto first responders, i.e., police or EMT personnel. Typically, the INand IM are administered by first responders arriving at the scene, thetime for which can vary from 5 to 15 minutes and up to 30 minutes afteran individual suffering from opioid overdose has been found unconsciousand emergency services have been contacted. Consequentially, anindividual exhibiting symptoms of respiratory depression associated withknown or suspected opioid overdose may live or die simply depending uponwhen the first-responders reach the individual's physical location.

Further, given the expense of the currently marketed naloxone dosageforms, naloxone can be a budget buster for municipalities, makingavailability a problem even among first responders. A more affluentmunicipality may supply Narcan® IN to first responders, while a lessaffluent, adjacent municipality may not have sufficient revenue tosupply Narcan® IN to first responders. Thus, there is a long-felt needfor a lower cost alternative, which can be more widely available.

Narcan® IN became the first FDA approved non-injectable naloxone productfor the treatment of opioid overdose. EMS programs have now moved towardintranasal administration of naloxone to avoid needle stick risksbecause many patients needing naloxone are injection drug users and 80%of this patient population in large metropolitan areas is Hepatitis C orHIV positive.

Narcan® IN is supplied in 2 mg or 4 mg dosage strength metered sprays of0.1 milliliter volume. The current Narcan® IN formulation includesinactive ingredients including benzalkonium chloride (preservative),disodium ethylenediaminetetraacetate (stabilizer), sodium chloride,hydrochloric acid to adjust pH, and purified water. The pH range forNarcan® IN is 3.5 to 5.5. Such a pH range of 3.5 to 5.5 is highly acidicand may irritate the nasal mucosa. Further, because Narcan® is availablein nasal spray dispenser form, the formulation may drip out of the nasalcavity resulting in the dosage being swallowed and not available fortreating respiratory arrest.

Further, in many circumstances intranasal administration may not besuitable for persons unresponsive due to opioid overdose. Examplesinclude cases involving damage to, or obstruction of, the nasal mucosaor cavity from habitual snorting of cocaine, opioids, or othersubstances of abuse. In a study by Barton et al., it was shown that 9out of 52 subjects (17%) who received intranasal naloxone for suspectedopioid overdose were unresponsive to the treatment. See, e.g., Erik D.Barton, et al., Efficacy of intranasal naloxone as a needlelessalternative for treatment of opioid overdose in the prehospital setting,29 J. EMERGENCY MEDICINE 265 (2005), incorporated by reference herein inits entirety. Five (56%) of the nine non-responders had epistaxis (n=2),nasal mucus (n=1), trauma (n=1), or septal abnormality (n=1), while noneof the intranasal naloxone responders had any nasal abnormalities. Inaddition, excess mucus production and changes in mucociliary clearancerates may also affect bioavailability. During a common cold or sinuscongestion, the efficacy of intranasal medication is frequentlycompromised. Accordingly, a route of administration aside fromintramuscular and intranasal is an unmet need for out-of-hospitalmanagement of opioid overdose. Accordingly, there remains an unmet needin opioid overdose therapy. If new, safe, less expensive and effectiveliquid, gel, or semi-solid formulations of naloxone for sublingualand/or buccal administration could be developed, this would represent auseful contribution to the art. Further, if new methods could be foundof treating known or suspected opioid overdoses by administeringsublingually and/or buccally a liquid, gel, or semi-solid formulationcontaining naloxone, this would also represent a useful contribution tothe art and save thousands of lives.

SUMMARY OF THE INVENTION

In an embodiment, the present disclosure provides a liquid, gel orsemi-solid pharmaceutical comprising from about 1% to about 25% ofnaloxone base, or a derivative thereof, by the total mass of thecomposition; and from about 50% to about 99% of one or more non-aqueoussolvents selected from the group consisting of oleic acid, liquidpolyethylene glycol, propylene glycol, and ethanol, or mixtures thereof,by the total mass of the composition; wherein the naloxone base, orderivative thereof, is completely and homogeneously dissolved in the oneor more non-aqueous solvents. In some embodiments, the compositionfurther comprises from about 1% to about 25% of a viscosity adjustingagent, by the total mass of the composition.

In another embodiment, the present disclosure provides pharmaceuticalcompositions comprising: naloxone base, or an isomer or a derivativethereof, in an amount of from about 1 mg to about 20 mg; and one or morenon-aqueous solvents selected from the group consisting of oleic acid,liquid polyethylene glycol, propylene glycol, and ethanol, or mixturesthereof, in a combined amount of from about 50 mg to about 500 mg;wherein the naloxone base, or isomer or derivative thereof, iscompletely and homogeneously dissolved in the one or more selectednon-aqueous solvents.

For clarification, naloxone base is completed dissolved in thisnon-aqueous solvent system or vehicle to form a true single-phasesolution. As such, this vehicle composition does not include emulsifiersor surfactants, which would result in two-phase systems such as anemulsion, dispersion, or liquid crystalline systems or precursors tosuch systems, e.g., self-emulsifying drug delivery systems.

In another embodiment, the present disclosure provides pharmaceuticalcompositions for sublingual or buccal delivery further comprising one ormore viscosity adjusting agents selected from the group consisting ofcalcium silicate, acacia, carbomers, carboxymethylcellulose sodium,silicon dioxide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, hypromellose, methylcellulose,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols ormixtures thereof, in a combined amount of from about 1 mg to about 125mg.

In yet another embodiment, the present disclosure providespharmaceutical compositions for sublingual or buccal delivery, whereinthe pharmaceutical compositions contain a concentration of naloxonebase, or an isomer or a derivative thereof, in the one or morenon-aqueous solvents, of from about 1% to about 25%, as a percentage ofmass of the naloxone base, or isomer or derivative thereof, in thecombined mass of the one or more non-aqueous solvents.

In yet another embodiment, the present disclosure providespharmaceutical compositions for sublingual or buccal delivery, whereinthe pharmaceutical composition provides a plasma concentration ofnaloxone of at least about 1 ng/mL within about 10 minutes followingsublingual or buccal administration of the pharmaceutical composition toan individual.

In yet another embodiment, the present disclosure providespharmaceutical compositions for sublingual or buccal delivery to anindividual, wherein the individual is exhibiting symptoms of respiratorydepression associated with known or suspected opioid overdose.

In yet another embodiment, the present disclosure providespharmaceutical compositions configured to be administered sublinguallyor buccally to an individual from a single unit dosage form containerselected from the group consisting of a spray dispenser, an oralsyringe, or a blow-fill-seal unit dose dispenser.

In yet another embodiment, the present disclosure provides methods fortreating an individual exhibiting symptoms of respiratory depressionassociated with known or suspected opioid overdose that can include thesteps of: (a) providing a single unit dosage form including a solutionof naloxone base, or a derivative thereof, as a completely,homogeneously dissolved solute in one or more non-aqueous solvents; and(b) administering the single unit dosage form sublingually or buccallyto the individual.

In yet another embodiment, the present disclosure provides methods fortreating an individual exhibiting symptoms of respiratory depressionassociated with known or suspected opioid overdose, wherein the singleunit dosage form further includes one or more viscosity adjustingagents.

In yet another embodiment, the present disclosure provides methods fortreating an individual exhibiting symptoms of respiratory depressionassociated with known or suspected opioid overdose, further includingthe step of: (c) repeating step (b) if the individual does not recoverfrom respiratory depression within about 2 to 5 minutes following theadministering of step (b).

In yet another embodiment, the present disclosure provides methods fortreating an individual exhibiting symptoms of respiratory depressionassociated with known or suspected opioid overdose, wherein the plasmaconcentration of naloxone in the individual is at least about 1 ng/mLwithin about 15 minutes (e.g., within about 10 minutes) following theadministering step (b).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the free naloxone plasma concentration over timefollowing administration of naloxone compositions prepared according toan embodiment of the present invention as compared to intramuscular(“IM”) and intranasal (“IN”) administration of commercially availableformulations of naloxone.

DETAILED DESCRIPTION

The present invention provides naloxone compositions and methods oftreatment of opiate overdose induced respiratory depression. In certainembodiments, the present invention provides pharmaceutical formulationsfor rapid transmucosal delivery of naloxone base, e.g., for sublingualor buccal administration at or near physiological pH.

Transmucosal delivery includes, but is not necessarily limited to, theoral, tongue, esophagus, and nasal mucosa. Buccal administration is atopical route of administration by which a drug held or applied in thebuccal area (i.e., in the oral cavity, between the gum and the cheek ofan individual) permeates through the oral mucosa and enters directlyinto the bloodstream. Sublingual administration is a transmucosal routeof administration by which a drug product is placed under the tongue ofan individual and permeates through the oral mucosa and enters directlyinto the bloodstream.

The physiological pH values of the various transmucosal membranes varyconsiderably. The physiological pH of the gastrointestinal tractincreases along its length from about pH 1 in the stomach to about pH 8in the colon. Saliva has a pH of about 6.8. The pH of nasal fluidsranges from about 5.5 to about 6.5. Without being bound by theory, thepresent invention is designed to provide rapid transmucosal absorptionof naloxone base in the pH range specific to the target mucosal tissue,which avoids local irritation. Accordingly, transmucosal absorption ofliquid, gel, and semi-solid formulations of naloxone base, according toembodiments of the present invention, occurs independently of local pHas naloxone base is insoluble in water and therefore cannot change thepH of saliva or mucosal tissue. Without being bound by theory,transmucosal delivery of liquid, gel, and semi-solid formulations ofnaloxone base, according to embodiments of the present invention,requires only the development of a hydration or dielectric gradient fromwater in the saliva. This results in the formation of a supersaturatednaloxone solution as water from saliva interacts with the non-aqueousdrug vehicle, which increases the driving force for transmucosal drugabsorption.

Naloxone hydrochloride is not natively amenable to sublingual deliveryeven though it is soluble in water. This is supported by the lownaloxone plasma levels obtained from Suboxone®, a combinationbuprenorphine/naloxone hydrochloride sublingual tablet (SLT). Naloxone'smean absolute bioavailability from Suboxone® SLT is approximately 3%.Mean peak naloxone plasma levels (Cmax) averaged 0.28 ng/mL for the 4 mgnaloxone strength Suboxone® (Suboxone® Tablet 2018 Patient PackageInsert).

The 6 mg naloxone composition described in the Examples below, whenadministered sublingually, had peak naloxone levels of 2.6 ng/mL, or 3.7times greater when dose adjusted to the 4 mg naloxone strength Suboxone®SLT. This pharmacokinetic (PK) data substantiated that this novel drugdelivery technology significantly increases naloxone's bioavailabilityover Suboxone®.

In certain embodiments, the present invention provides, inter alia,processes for preparing rapid onset transmucosal naloxone deliverysystems (or isomers or derivatives thereof).

Compounding the liquid, gel, or semi-solid formulation, according toembodiments of the present invention, includes forming a homogeneoussolution of naloxone base and a solvent vehicle including one or morenon-aqueous solvents, in which naloxone is a completely dissolvedsolute. In certain embodiments, the liquid, gel, or semi-solidformulation may further include one or more viscosity adjusting agents.Without being bound by theory, increasing the drug vehicle viscosityincreases the residence time in the oral cavity and thereby minimizesthe amount of naloxone that will be swallowed. For clarification,naloxone base is completed dissolved in this non-aqueous solvent systemor vehicle to form a true single-phase solution. As such, this vehiclecomposition does not include emulsifiers or surfactants, which wouldresult in two-phase systems such as an emulsion, dispersion, or liquidcrystalline systems or precursors to such systems, e.g.,self-emulsifying drug delivery systems.

In embodiments of the present invention, the non-aqueous solvent systemincluding one or more non-aqueous solvents may include one or moresolvents selected from the group consisting of oleic acid, polyethyleneglycol, propylene glycol, ethanol, or mixtures thereof. Polyethyleneglycols that are liquids under ambient conditions may be used assolvents in the non-aqueous solvent systems of embodiments of thepresent invention and may be selected from the group consisting of PEGshaving a molecular weight of 600 or less, e.g., PEG 200, PEG 300, PEG400, and PEG 600.

As described herein, the formulations comprise one or more non-aqueoussolvents and are therefore substantially free of water; however, theformulations may comprise a small amount of water, such as incidentalwater content due to absorption of water from the environment, includingfrom use of excipients that contain an incidental amount of water. Forexample, some commercially available PEGs may contain up to about 2%water.

In certain embodiments of the present invention, the liquid, gel, orsemi-solid formulations may include one or more viscosity adjustingagents selected from the group consisting of calcium silicate, acacia,carbomers, carboxymethylcellulose sodium, silicon dioxide, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol or mixtures thereof. Polyethylene glycols that aresolids under ambient conditions may be used as viscosity adjustingagents in the non-aqueous solvent vehicle of embodiments of the presentinvention, and may be selected from the group consisting of PEGs havinga molecular weight of greater than 600, e.g., PEG 1000, 1500, 2000.Although one or more viscosity adjusting agents are within the purviewof the present invention any functionally equivalent to one or moreviscosity adjusting agents selected from the group consisting of calciumsilicate, acacia, carbomers, carboxymethylcellulose sodium, silicondioxide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, hypromellose, methylcellulose,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, andmixtures thereof.

In one embodiment, the present invention is directed to liquid, gel, orsemi-solid formulations including an effective amount of naloxone base,or isomer or derivative thereof, and a non-aqueous solvent systemincluding one or more non-aqueous solvents.

In another embodiment, the present invention is directed to liquid, gel,or semi-solid formulations including an effective amount of naloxonebase, or isomer or derivative thereof, a non-aqueous solvent systemincluding one or more non-aqueous solvents, and one or more viscosityadjusting agents.

In various embodiments, the present invention is directed to a liquid,gel, or semi-solid formulation including: naloxone base, or an isomer orderivative thereof, in an amount of from about 1% to about 25% of thetotal mass of the formulation; and one or more non-aqueous solvents in acollective amount of from about 50% to about 99% of the total mass ofthe formulation. Optionally, the formulation may further comprise fromabout 1% to about 25% of one or more viscosity adjusting agents.

In various embodiments, the formulation comprises from about 1% to about15% or from about 1% to about 10% of naloxone base, by the total mass ofthe formulation. In various embodiments, the formulation comprises acollective amount of from about 60% to about 99%, from about 70% toabout 99%, or from about 75% to about 99% of one or more non-aqueoussolvents, by the total mass of the formulation. In other variousembodiments, the formulation comprises a collective amount of from about50% to about 98%, from about 60% to about 98%, from about 70% to about98%, or from about 75% to about 98% of one or more non-aqueous solvents,by the total mass of the formulation. And in yet other variousembodiments, the formulation comprises a collective amount of from about50% to about 90%, from about 60% to about 90%, from about 70% to about90%, or from about 75% to about 90% of one or more non-aqueous solvents,by the total mass of the formulation. In various embodiments, theformulation comprises from about 9% to about 25% or from about 9% toabout 20% of the one or more viscosity adjusting agents, by the totalmass of the formulation.

In a preferred embodiment of the liquid, gel, or semi-solid formulation,the one or more non-aqueous solvents are selected from the groupconsisting of oleic acid and ethanol. In another preferred embodiment ofthe liquid, gel, or semi-solid formulation, the formulation includesoleic acid in an amount of from about 70% to about 95% of the total massof the formulation. In yet another preferred embodiment of the liquid,gel, or semi-solid formulation, the formulation includes ethanol in anamount of from about 0.01% to about 30% of the total mass of theformulation. In one embodiment, the formulation includes naloxone base,or an isomer or derivative thereof, in an amount from about 1% to about15% of the total mass of the formulation. In one embodiment, theformulation includes naloxone base, or an isomer or derivative thereof,in an amount from about 2% to about 10% of the total mass of theformulation.

In another embodiment, the present invention is directed to a liquid,gel, or semi-solid formulation including: naloxone base, or a derivativethereof, in an amount of from about 1% to about 30% of the total mass ofthe formulation; one or more non-aqueous solvents in a collective amountof from about 65% to about 98% of the total mass of the formulation; andoptionally one or more viscosity adjusting agents in a collective amountof from about 1% to about 20% of the total mass of the formulation.

In one preferred embodiment of the liquid, gel, or semi-solidformulation, the one or more non-aqueous solvents are selected from thegroup consisting of oleic acid and ethanol and a combination thereof. Inanother preferred embodiment of the liquid, gel, or semi-solidformulation, the formulation includes oleic acid in an amount of fromabout 60% to about 90% of the total mass of the formulation. In yetanother preferred embodiment of the liquid, gel, or semi-solidformulation, the formulation includes ethanol in an amount of from about5% to about 30% of the total mass of the formulation. In anotherembodiment of the liquid, gel, or semi-solid formulation, the one ormore viscosity adjusting agents is silicon dioxide. In yet anotherembodiment of the liquid, gel, or semi-solid formulation, theformulation includes silicon dioxide in an amount of from about 1% toabout 25% of the total mass of the formulation.

In another preferred embodiment of the liquid, gel, or semi-solidformulation, the one or more non-aqueous solvents are selected from thegroup consisting of polyethylene glycol, propylene glycol, ethanol, andany combination thereof. In another preferred embodiment of the liquid,gel, or semi-solid formulation, the formulation includes polyethyleneglycol in an amount of from about 60% to about 99% of the total mass ofthe formulation. In yet another preferred embodiment of the liquid, gel,or semi-solid formulation, the formulation includes propylene glycol inan amount of from about 5% to about 20% of the total mass of theformulation. In yet another preferred embodiment of the liquid, gel, orsemi-solid formulation, the formulation includes ethanol in an amount offrom about 5% to about 25% of the total mass of the formulation. Inanother embodiment of the liquid, gel, or semi-solid formulation, theone or more viscosity adjusting agents is silicon dioxide. In yetanother embodiment of the liquid, gel, or semi-solid formulation, theformulation includes silicon dioxide in an amount of from about 1% toabout 25% of the total mass of the formulation.

In another embodiment, the liquid, gel, or semi-solid formulationcomprises from about 1% to about 25% of naloxone base, and from about60% to about 99% polyethylene glycol, and optionally from about 5% toabout 20% propylene glycol, and optionally from about 5% to about 25%ethanol.

In some embodiments, the formulation is a liquid formulation. In otherembodiments, the formulation is a gel formulation. And in yet otherembodiments, the formulation is a semisolid formulation.

In some embodiments, the liquid, gel, or semi-solid formulationsdescribed herein consist of, or consist essentially of, the componentsdescribed. For example, in some embodiments the liquid, gel, orsemi-solid formulations consist of, or consist essentially of: naloxonebase, or isomer or derivative thereof, in an amount of from about 1% toabout 25% of the total mass of the formulation; and one or morenon-aqueous solvents in a collective amount of from about 50% to about99% of the total mass of the formulation; and optionally from about 1%to about 25% of one or more viscosity adjusting agents.

In embodiments of the present invention, the liquid, gel, or semi-solidformulation may be packaged in such manner as to aid in maintainingstability of the formulation in a single-unit dose dispenser. Packagingmethods and materials may include, but are not limited to, spraydispensers, oral syringes, blow-fill-seal (“BFS”) unit-dose dispensers,and other dosage form containers suitable for direct administration ofthe liquid, gel, or semi-solid formulations of the present invention tothe oral or nasal mucosa. The packaging methods and materials for theliquid, gel, or semi-solid formulations of the present invention employmanufacturing techniques familiar to one versed in the art offormulating and processing pharmaceutical dosage forms.

In embodiments of the present invention, a rapid, bolus, transmucosaldose of naloxone base is provided that is formulated as a liquid, gel,or semi-solid. In certain embodiments, the rapid, bolus, transmucosaldosage form releases naloxone relatively quickly, resulting intransmucosal absorption of naloxone in less than about 30 minutes. Inother embodiments, transmucosal absorption of naloxone occurs in lessthan about 15 minutes. In other embodiments, transmucosal absorption ofnaloxone occurs in less than about 12.5 minutes. In other embodiments,transmucosal absorption of naloxone occurs in less than about 10minutes. In other embodiments, transmucosal absorption of naloxoneoccurs in less than about 7.5 minutes. In other embodiments,transmucosal absorption of naloxone occurs in less than about 5 minutes.In other embodiments, transmucosal absorption of naloxone occurs in lessthan about 4 minutes. In other embodiments, transmucosal absorption ofnaloxone occurs in less than about 3 minutes. In other embodiments,transmucosal absorption of naloxone occurs in less than about 2.5minutes. In other embodiments, transmucosal absorption of naloxoneoccurs in less than about 2 minutes. In other embodiments, transmucosalabsorption of naloxone occurs in less than about 1.5 minutes. In otherembodiments, transmucosal absorption of naloxone occurs in less thanabout 1 minute. In other embodiments, transmucosal absorption ofnaloxone occurs in less than about 0.5 minutes.

The naloxone liquid, gel, or semi-solid formulations according toembodiments of the present invention are useful in the acute treatmentof respiratory depression in an individual exhibiting symptomsassociated with known or suspected opioid overdose.

In an embodiment, a method of treating respiratory depression in anindividual exhibiting symptoms associated with known or suspected opioidoverdose can include the steps of:

(a) providing a single dosage form of a liquid, gel, or semi-solidformulation including a solution of naloxone base, or an isomer or aderivative thereof, as a completely, homogeneously dissolved solute in anon-aqueous solvent system; and

(b) administering the single dosage sublingually or buccally to theindividual.

More generally, a formulation, composition or dosage described hereinmay be administered transmucosally to the oral, esophageal or nasalmucosa. For example, the dosage may be administered by a blow-fill-sealunit dose dispenser, oral syringe, or spray delivery.

The process described herein effects a method of treating respiratorydepression in an individual exhibiting symptoms associated with known orsuspected opioid overdose.

In another embodiment, a method of treating respiratory depression in anindividual exhibiting symptoms associated with known or suspected opioidoverdose can include the steps of:

(a) providing a single dosage form of a liquid, gel, or semi-solidformulation including a solution of naloxone base, isomer or aderivative thereof, as a completely, homogeneously and completelydissolved solute in a non-aqueous solvent system, and a viscosityadjusting agent; and

(b) administering the single dosage form sublingually or buccally to theindividual.

The process described herein effects a method of treating respiratorydepression in an individual exhibiting symptoms associated with known orsuspected opioid overdose. In yet another embodiment, a method oftreating respiratory depression in an individual exhibiting symptomsassociated with known or suspected opioid overdose can include the stepsof:

(a) providing a single dosage form of a liquid, gel, or semi-solidformulation including a solution of naloxone base, isomer or aderivative thereof, as a completely, homogeneously dissolved solute in anon-aqueous solvent system;

(b) administering the single dosage form sublingually or buccally to theindividual; and

(c) repeating step (b) if the individual does not recover fromrespiratory depression within from about 2 to about 5 minutes followingthe administering of step (b).

The process described herein effects a method of treating respiratorydepression in an individual exhibiting symptoms associated with known orsuspected opioid overdose. In yet another embodiment, a method oftreating respiratory depression in an individual exhibiting symptomsassociated with known or suspected opioid overdose can include the stepsof:

(a) providing a single dosage form of a liquid, gel, or semi-solidformulation including a solution of naloxone base, or an isomer or aderivative thereof, as a completely, homogeneously dissolved solute in anon-aqueous solvent system, and a viscosity adjusting agent;

(b) administering the single dosage form sublingually or buccally to theindividual; and

(c) repeating step (b) if the individual does not recover fromrespiratory depression within from about 2 to about 5 minutes followingthe administering of step (b).

The process described herein effects a method of treating respiratorydepression in an individual exhibiting symptoms associated with known orsuspected opioid overdose.

Single dosage forms of the liquid, gel, or semisolid formulationsaccording to the embodiments of the present invention including naloxonebase, or an isomer or a derivative thereof, may contain an effectiveamount of naloxone base, or an isomer or a derivative thereof. Theeffective amount of naloxone base, or derivative thereof, is sufficientto treat respiratory depression in an individual exhibiting symptomsassociated with known or suspected opioid overdose. In certainembodiments of the present invention, a single dosage form may containnaloxone base, or an isomer or a derivative thereof, in an amount ofabout 1 mg to about 20 mg. In other embodiments of the presentinvention, a single dosage form may contain naloxone base, or an isomeror a derivative thereof, in an amount of about 5 mg to about 15 mg. Inother embodiments of the present invention, a single dosage form maycontain naloxone base, isomer or a derivative thereof, in an amount ofabout 10 mg. In other embodiments of the present invention, a singledosage form may contain naloxone base, isomer or a derivative thereof,in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg,about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

In certain embodiments of the present invention, the concentration ofnaloxone base, or an isomer or a derivative thereof, as completely andhomogenously dissolved solute in a non-aqueous solvent system, as apercentage of mass of naloxone base to total mass of solvent system, isfrom about 1% to about 25%. In other embodiments of the presentinvention, the concentration of naloxone base, or a derivative thereof,as completely and homogeneously dissolved solute in a non-aqueoussolvent system, as a percentage of mass of naloxone base to total massof solvent system, is from about 5% to about 20%. In other embodimentsof the present invention, the concentration of naloxone base, or anisomer or a derivative thereof, as completely and homogeneouslydissolved solute in a non-aqueous solvent system, as a percentage ofmass of naloxone base to total mass of solvent system, is from about 10%to about 15%. In other embodiments of the present invention, theconcentration of naloxone base, or a derivative thereof, as completelyand homogeneously dissolved solute in a non-aqueous solvent system, as apercentage of mass of naloxone base to total mass of solvent system, isfrom about 1% to about 10%. In other embodiments of the presentinvention, the concentration of naloxone base, or a derivative thereof,as completely and homogeneously dissolved solute in a non-aqueoussolvent system, as a percentage of mass of naloxone base to total massof solvent system, is from about 10% to about 25%. In other embodimentsof the present invention, the concentration of naloxone base, or aderivative thereof, as completely and homogeneously dissolved solute ina non-aqueous solvent system, as a percentage of mass of naloxone baseto total mass of solvent system, is about 1%, about 2%, about 3%, about4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about24%, or about 25%.

The term “recover,” as used herein, alone or in combination with otherterms, unless stated otherwise, means observable amelioration ofphysical symptoms conventionally associated with respiratory depression,including, but not limited to, reversal of respiratory depression.

The term “effective amount,” as used herein, alone or in combinationwith other terms, means an amount necessary to treat an individual inneed thereof.

Derivatives of naloxone that can be used in accordance with embodimentsof the present invention include, but are not limited to: 3-O-acyl,phenylhydrazone, and methiodide derivatives of naloxone.

3-O-Acyl derivatives of naloxone have the following general chemicalstructure:

wherein R is selected from the group consisting of (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, and (C₂-C₁₅) alkynyl.

The phenylhydrazone derivative of naloxone has the following chemicalstructure:

The methiodide derivative of naloxone has the following chemicalstructure:

It will be readily understood that the compositions, ingredients,solvents, agents, formulations, processes, and methods of the presentinvention, as generally described herein, are arranged and designed in awide variety of dosage forms and formulations. The compositions,ingredients, solvents, agents, formulations, processes, and methodsdescribed herein in the embodiments above may be further understood inconnection with the following Examples. In addition, the followingnon-limiting Examples are intended to illustrate the invention. However,the person skilled in the art will appreciate that it may be necessaryto vary the procedures for any given embodiment of the invention, e.g.,vary the order or steps of the methods and/or the compositions,ingredients, solvents, agents, and/or formulations used.

Example 1A

In an embodiment, the present invention provides a liquid solutiondosage form composition, having a total mass of about 62.6 milligrams(“mg”), including 6 mg of naloxone base, oleic acid, and ethanol. Insuch an embodiment, naloxone is mixed with oleic acid and ethanol untilthe naloxone is completely dissolved in the oleic acid and ethanol so asto form a homogeneous solution. An exemplary formulation in accordancewith this embodiment includes mass amounts of ingredients according toTable 1A, below.

TABLE 1A 6 mg Naloxone Liquid Solution Dosage Form CompositionIngredient Mass Amount (mg/dose) Naloxone Base 6.0 Oleic acid 51.0Ethanol 5.6 Total Mass (mg) 62.6

Example 1B 6 mg Naloxone Liquid Solution Dosage Form Composition

In an embodiment, the present invention provides a viscous liquidsolution dosage form composition, having a total mass of about 72.6milligrams (“mg”), including 6.0 mg of naloxone base, oleic acid,ethanol and silicon dioxide. An exemplary formulation in accordance withthis embodiment includes mass amounts of ingredients according to Table1B, below.

TABLE 1B 6 mg Naloxone Liquid Solution Dosage Form CompositionIngredient Mass Amount (mg/dose) Naloxone Base 6.0 Oleic acid 51.0Ethanol 5.6 Silicon Dioxide 10.0 Total Mass (mg) 72.6

Example 2 10 mg Naloxone Liquid Solution Dosage Form Composition

In an embodiment, the present invention provides a liquid solutiondosage form composition, having a total mass of about 250 mg, including10 mg of naloxone base, and polyethylene glycol 300. In such anembodiment, naloxone is mixed with polyethylene glycol 300 until thenaloxone is completely dissolved in the polyethylene glycol 300 so as toform a homogeneous solution. An exemplary formulation in accordance withthis embodiment includes mass amounts of ingredients according to Table2, below.

TABLE 2 Ingredient Mass Amount (mg/dose) Naloxone Base 10.0 Polyethyleneglycol 300 240.0 Total Mass (mg) 250.0

Example 3A 10 mg Naloxone Liquid Solution Dosage Form Composition

In an embodiment, the present invention provides a liquid solutiondosage form composition, having a total mass of about 126 mg, including10 mg of naloxone base, polyethylene glycol 300, propylene glycol, andethanol. In such an embodiment, naloxone is mixed with polyethyleneglycol 300, propylene glycol, and ethanol until the naloxone iscompletely dissolved in the polyethylene glycol 300, propylene glycol,and ethanol so as to form a homogeneous solution. An exemplaryformulation in accordance with this embodiment includes mass amounts ofingredients according to Table 3A, below.

TABLE 3A Ingredient Mass Amount (mg/dose) Naloxone Base 10.0Polyethylene glycol 300 90.0 Propylene glycol 10.8 Ethanol 15.2 TotalMass (mg) 126.0

Example 3B 10 mg Naloxone Liquid Solution Dosage Form Composition

In an embodiment, the present invention provides a viscous liquidsolution dosage form composition, having a total mass of about 145 mg,including 10 mg of naloxone base, polyethylene glycol 300, propyleneglycol, ethanol, and silicon dioxide. An exemplary formulation inaccordance with this embodiment includes mass amounts of ingredientsaccording to Table 3B, below.

TABLE 3B Ingredient Mass Amount (mg/dose) Naloxone Base 10.0Polyethylene glycol 300 90.0 Propylene glycol 10.8 Ethanol 15.2 SiliconDioxide 19.0 Total Mass (mg) 145.0

Example 4

The pharmacokinetics of a naloxone 6 mg composition of Example 1B wasinvestigated when administered sublingually. The plasma concentration ofnaloxone following administration are presented in FIG. 1. Theintramuscular (“IM”) and 6 mg composition demonstrated lag times (i.e.,the time needed to exceed 0.5 ng/mL) of between 5 and 10 minutes. The 6mg dose showed greater naloxone plasma concentration levels at 15minutes compared to that of the intramuscular (i.e., 0.92 ng/mL and 0.70ng/mL, respectively). The C_(max) was greater for sublingualadministration, being 2.6 ng/mL vs. 0.75 ng/mL for the IM. Thus,transmucosal absorption of 6 mg composition from administrationsublingually exceeded the 0.4 mg IM administration drug exposure. Thepharmacokinetics of a naloxone 10 mg composition of Example 3B wereinvestigated when administered both sublingually and on top of thetongue. The plasma concentration of naloxone following administration ofthe 10 mg composition sublingually and on the top of the tongue arepresented in FIG. 1. The intramuscular (“IM”) and both 10 mgcompositions demonstrated lag times (i.e., the time needed to exceed 0.5ng/mL) of between 5 and 10 minutes. Both 10 mg administrations showedgreater naloxone plasma concentration levels at 10 minutes compared tothat of the intramuscular, i.e. 2.5 ng/mL (sublingual), 0.94 ng/mL (ontongue), and 0.58 ng/mL, respectively). The C_(max) was greater foradministration on top of the tongue, 5.2 ng/mL, vs. 3.9 ng/mLsublingually. The absorption of naloxone took a few more minutes on topof the tongue; however, the maximum plasma concentration of naloxoneachieved was greater than for administration sublingually and forintranasal (“IN”) spray. Without being bound by theory, these resultsmay be explained by mucosal physiology. The sublingual mucosa is thin(˜100 μm), not keratinized, and has a lower surface area, while themucosa of the tongue is thicker (˜200 μm), keratinized, and has agreater surface area due to papillae. Thus, transmucosal absorption fromadministration either sublingually or on top of the tongue providescomparable drug exposure and exceeds the 0.4 mg IM administration drugexposure.

Pharmacokinetic data from the naloxone 6 mg and 10 mg compositions alsodemonstrated greater exposure compared to the 0.4 mg IM injection,thereby exceeding the Reference Listed Drug (“RLD”) standard. The 6 mgstrength peak naloxone plasma concentration levels were 3.5 timesgreater than that of the IM injection and 5 to 7 times greater for the10 mg strength. The IM and IN pharmacokinetic data used for thiscomparison were obtained from Narcan® IN spray Clinical PharmacologyReview in 29 subjects. A graph of naloxone plasma concentration levelscomparing a 6 mg composition (n=1) to the 0.4 mg IM injection and 4 mgIN spray with 90% CI is depicted in FIG. 1. Naloxone plasmaconcentration levels beyond the 10-minute time point substantiallyexceeded the IM plasma concentration levels and the 10 mg strength wascomparable to the IN spray plasma concentration levels.

The plasma curve for the 10 mg compositions from sublingualadministration is similar to that of the IN spray. The lag time isseveral minutes longer for the sublingual administration; however, bothcurves reached 1.5 ng/mL naloxone plasma concentration levels within 2minutes of the other (i.e., 7 minutes for the 10 mg composition vs. 5minutes for the intranasal spray). Similarly, the 2.5 ng/mL plasmaconcentration level is reached at 10 minutes for sublingualadministration vs. 8 minutes for the intranasal spray. Both the 6 mg and10 mg compositions and the IN spray reach T_(max) at 20 minutes. The INspray has a slightly higher C_(max) of 4.5 ng/mL compared to 3.9 ng/mLfor the 10 mg composition administered sublingually. Priorpharmacokinetic studies with similar formulations have shown goodcorrelation between dose and C_(max). Therefore, a higher C_(max) may beexpected by increasing the dose of naloxone, should that be deemeddesirable.

The use of the terms “a,” “an,” “the,” and similar referents in thecontext of describing the presently claimed invention (especially in thecontext of the claims) are to be construed to cover both the singularand the plural, unless otherwise indicated herein or clearlycontradicted by context. Recitation of ranges of values herein aremerely intended to serve as a shorthand method of referring individuallyto each separate value falling within the range, unless otherwiseindicated herein, and each separate value is incorporated into thespecification as if it were individually recited herein. Use of the term“about” is intended to describe values either above or below the statedvalue in a range of approximately ±10%; in other embodiments the valuesmay range in value either above or below the stated value in a range ofapproximately ±5%; in other embodiments the values may range in valueeither above or below the stated value in a range of approximately ±2%;in other embodiments the values may range in value either above or belowthe stated value in a range of approximately ±1%. The preceding rangesare intended to be made clear by context, and no further limitation isimplied. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate the invention and does not pose a limitation on the scope ofthe invention unless otherwise claimed. No language in the specificationshould be construed as indicating any non-claimed element as essentialto the practice of the invention.

While in the foregoing specification this invention has been describedin relation to certain embodiments thereof, and many details have beenput forth for the purpose of illustration, it will be apparent to thoseskilled in the art that the invention is susceptible to additionalembodiments and that certain of the details described herein can bevaried considerably without departing from the basic principles of theinvention.

All references cited herein are incorporated by reference in theirentireties. The present invention may be embodied in other specificforms without departing form the spirit or essential attributes thereofand, accordingly, reference should be made to the appended claims,rather than to the foregoing specification, as indicating the scope ofthe invention.

1-9. (canceled)
 10. A method for treating an individual exhibitingsymptoms of respiratory depression associated with known or suspectedopioid overdose comprising: administering a pharmaceutical compositionsublingually or buccally to the individual, wherein the pharmaceuticalcomposition is a liquid, gel or semi-solid pharmaceutical compositioncomprising from about 1% to about 25% of naloxone base, or an isomer ora derivative thereof, by the total mass of the composition; and fromabout 50% to about 99% of one or more non-aqueous solvents selected fromthe group consisting of oleic acid, liquid polyethylene glycol,propylene glycol, and ethanol, or mixtures thereof, by the total mass ofthe composition; wherein the composition is substantially free of water;and wherein the naloxone base, or isomer or derivative thereof, iscompletely and homogeneously dissolved in the one or more non-aqueoussolvents.
 11. The method of claim 10, wherein the pharmaceuticalcomposition further comprises one or more viscosity adjusting agents.12. The method of claim 10, further comprising: repeating administrationof the pharmaceutical composition if the individual does not recoverfrom respiratory depression within from about 2 to about 5 minutesfollowing administration.
 13. The method of claim 10, wherein the plasmaconcentration of naloxone in the individual is at least about 1 ng/mL inless than about 10 minutes following administration.
 14. The method ofclaim 11, wherein the one or more viscosity adjusting agents areselected from the group consisting of calcium silicate, acacia,carbomers, carboxymethylcellulose sodium, silicon dioxide, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol or mixtures thereof, by the total mass of thecomposition.
 15. The method of claim 10, wherein the pharmaceuticalcomposition is a liquid pharmaceutical composition.
 16. The method ofclaim 10, wherein the pharmaceutical composition is administered from asingle unit dosage form container selected from the group consisting ofa spray dispenser, an oral syringe, or a blow-fill-seal unit dosedispenser.